Shock of the new: treatment to beat sepsis

10 April 2018

Two leading names in pharma have signed an R&D agreement to develop a companion diagnostic test for septic shock that could help identify patients who are more likely to respond to treatment. Kerry Taylor-Smith speaks to Jean-Jacques Palombo, life-cycle leader and senior vice-president at Roche Diagnostics, and Margarita Salcedo-Magguilli, chief development officer at Inotrem, about septic shock and the issues facing the healthcare sector in beating it.

It is difficult to escape the stream of stories in the media about sepsis, a rare but life-threatening condition that can lead to multiple organ failure and even death if not treated quickly. Now often referred to as the ‘silent killer’, sepsis is the result of the body’s overwhelming response to an infection, and causes injury to its own tissues and organs.

Sepsis is often caused by a bacterial infection with the most commonly implicated being Staphylococci, Streptococcus pyrogenes, E. coli, and Pseudomonas aeruginosa, although fungi, viruses and parasites are sometimes cited as the source. Certain sections of the population are more vulnerable to the condition, including the very young or elderly, those with compromised immune systems such as cancer patients receiving treatment, or those who have recently experienced major trauma. People already in hospital with a serious illness, individuals who have just had surgery, or those with wounds or injuries resulting from an accident also have an increased risk of developing the condition.

The most common primary sites of infection resulting in sepsis are the lungs, where approximately 50% of all cases begin, the urinary tract, the abdomen and pelvis. Symptoms include fever, increased heart and breathing rates, and confusion. Other symptoms are related to a specific infection, such as a cough with pneumonia. In the most vulnerable, there may be no symptoms of a specific infection at all, and body temperature may be low or normal rather than high.

Estimates suggest 0.2 to 3 people out of every 1,000 develop sepsis yearly in the developed world and that it accounts for roughly 15% of in-hospital deaths in Western countries. The NHS estimates there are around 123,000 cases in England a year, resulting in 37,000 deaths. The rate of disease has been increasing, with more men suffering than women, although anyone can develop the disease after an injury or minor infection.

The severity of the sepsis determines the outcome – the risk of death from the disease is as high as 30%, rising up to 60% for those with severe sepsis and individuals who develop septic shock. The latter is a serious medical condition in which blood pressure drops dangerously low, and circulatory, cellular and metabolic abnormalities are seen, usually – though not always – as a result of sepsis.

Diagnostics is a key tool for physicians to understand the exact condition and state of a patient: it helps clarify which disease the patient suffers from, which pathway is activated within a certain type of disease.– Jean-Jacques Palombo

When blood pressure drops, the amount of blood and oxygen that reaches the body's organs is reduced, preventing the organs from working properly and causing them to shut down. Septic shock is the cause of death for around 40% of patients suffering from sepsis.

Those who survive often suffer cognitive and physical troubles, immune dysfunction, secondary infections, permanent organ damage, an impaired quality of life and depression or post-traumatic stress.

Need for diagnosis

Treatment for septic shock needs to begin as soon as possible, often in the intensive-care unit. But before that, a diagnosis must be made – and quickly. Developing suitable diagnostics to detect a disease or condition – not just sepsis and septic shock – is incredibly important, particularly when the illness has the potential to be life-threatening.

“Diagnostics is a key tool for physicians to understand the exact condition and state of a patient: it helps clarify which disease the patient suffers from, which pathway is activated within a certain type of disease,” says Jean-Jacques Palombo, life-cycle leader and senior vicepresident at Roche Diagnostics. “It can help measure the gravity, the need for an acute intervention or not. It can lead to designing a personalised treatment – drug and also disease management – based on the patient's own biology. I staunchly believe that we'll need a mix of multiple diagnostics technologies in the future in order to assess a given patient and make the right choices for them.”

He is not alone in this view. “Patients are by definition heterogeneous populations,” says Margarita Salcedo-Magguilli, chief development officer at Inotrem. “Treatments adapted to one patient may be inefficacious for another or even dangerous. It is important to count on diagnostic tools capable of identifying patients who would benefit from a given treatment, to know the optimal timing at which the treatment should be administered and the right dose that would be best suited to each patient.”

She adds, “In addition, the generation of diagnostic tools during the development of a therapeutic product will allow [us] to accelerate the availability of this treatment for patients, since demonstration of its efficacy will be better evaluated if patients who benefit from the treatment are identified during clinical trials. This will facilitate its approval by regulatory authorities.”

Joint venture

Efforts are being made to help the healthcare sector beat sepsis and septic shock by developing new diagnostics and drugs. Up until now, all drugs have failed, but Roche Diagnostics and Inotrem are hoping their new venture could change that. In November 2017, the two companies signed an R&D collaboration agreement to develop a companion test for septic shock. They aim to progress an in-vitro prototype assay for quantitative measurements of soluble TREM-1 (sTREM-1) in plasma samples from septic shock patients.

“Sepsis is the body’s overwhelming response to an infection, in most cases bacterial. Although sepsis starts with the infection, the high mortality comes from the body's abnormal response to that infection,” explains Palombo. “The body overreacts and creates an amplification loop of certain proteins, including the sTREM-1 protein. This inflammatory overreaction leads to organs such as the kidneys shutting down and vessels, as well as the heart, not responding.”

TREM proteins are a collection of cell surface receptors that take part in diverse cell processes, including inflammation, bone homeostasis, neurological development and coagulation. TREM-1 was the first to be identified and acts to amplify inflammation. Other proteins within the TREM family regulate the differentiation and function of macrophages, microglia, dendritic cells, osteoclasts and platelets.

STREM-1 is a protein that is released in the blood as part of the activation and immune amplification process mediated by the TREM-1 receptor. High concentrations of sTREM-1 in plasma have been associated with a negative outcome in septic shock patients, and measurement of sTREM-1 in blood could be a valuable indicator for the diagnosis and outcome prediction of septic shock patients.

LR12 is currently being studied in septic shock patients. Based on currently available data, LR12 does have the potential to significantly reduce the mortality and morbidity related to septic shock.– Margarita Salcedo-Magguilli

Joint venture

A phase 2 multicentre clinical trial is already under way, with Inotrem demonstrating the benefits of its lead compound Motrem, also known as LR12, in treating patients with septic shock. LR12 is a specific TREM-1 inhibitor and interferes in the binding of TREM-1 and its ligand. Consequently, LR12 inhibits the TREM-1-induced activation of leucocytes, or white blood cells, in a dose-dependent manner, conferring significant protective effects during septic shock. It is hoped the collaboration with Roche Diagnostics could lead to a companion diagnostic that supports the development of LR12.

“If the drug is successful, use of the test as a clinical assay would be straightforward,” says Palombo. “A patient ruled in for sepsis would receive a blood test that determines his or her level of sTREM-1. In commercial use, the test would be completed on a benchtop instrument, the Cobas e411, that's deployable across many geographies. In a clinical setting, a sepsis patient with the right blood or serum level of sTREM-1 would be eligible for the drug. The therapy would be administered as part of the standard of care for treating sepsis that includes surgery and antibiotics.”

“One of the keys of treatment success for septic shock patients is to intervene during the first hours of shock, in order to interrupt the amplification of the excessive response to infection,” explains Salcedo-Magguilli.

“The results should be ready very quickly and allow the clinician to rapidly decide whether or not to treat the patient with LR12, in addition to supportive and symptomatic treatments, based on the sTREM levels found in the patient's blood.

LR12 – a 12 amino-acid peptide prepared by chemical synthesis – is the only product targeting the underlying innate immune dysregulation that is a main cause of septic shock, says Salcedo- Magguilli. “LR12 is currently being studied in septic shock patients,” she adds.

“Based on currently available data, LR12 does have the potential to significantly reduce the mortality and morbidity related to septic shock, thereby addressing the medical need for a treatment addressing the causal pathological mechanism of the disease.”

Palombo says that although big pharmaceutical companies and venture capitals have been very active in the field of sepsis, they have so far been unsuccessful in their attempts. “We really hope this will be different with LR12 for Inotrem,” he says. “More importantly, we really hope this one will be different for the millions of people it could save each year, all around the globe.”

Common symptoms of sepsis include fever, increased heart rates and confusion, while other symptoms can be related to specific infections but in some patients, particularly the most vulnerable, there may be no symptoms at all.

Margarita Salcedo-Magguilli joined Inotrem in October 2015 and is responsible for the successful transition from pre-clinical to clinical stage, regulatory development, biomarker and companion diagnostic strategies, and drug product manufacturing. She has a PhD in immunology and tumour biology from the Karolinska Institute.

Although sepsis begins with an infection, it is the body's excessive response to that infection that can trigger severe illness, such as organs shutting down.

Jean-Jacques Palombo is a board-certified physician and received his MD from Paris University. He completed his medical residency in internal medicine at the Hopital Bichat in Paris before becoming a medical expert at Afssaps, the French FDA. He also earned an MBA from the Massachusetts Institute of Technology.

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